Management of metastatic colorectal cancer in patients ≥70 years - a single center experience

Background Age-standardized mortality rates for metastatic colorectal cancer (mCRC) are highest among elderly patients. In current clinical guidelines, treatment recommendations for this patient population are based on a limited number of clinical trials. Patients and methods In this monocentric, retrospective analysis we characterized patients aged ≥70 years undergoing systemic therapy for mCRC and overall survival (OS) was investigated. Results We included 117 unselected, consecutive mCRC patients aged ≥70 years undergoing systemic therapy for mCRC between February 2009 and July 2022. Median OS was 25.6 months (95% CI: 21.8-29.4). The median age was 78 years (range: 70-90) and 21%, 48%, 26% and 5% had an ECOG performance score of 0, 1, 2, and 3, respectively. The median number of systemic therapy lines was 2 (range: 1-5). The choice of first-line chemotherapy backbone (doublet/triplet versus mono) did not impact OS (HR: 0.83, p=0.50) or the probability of receiving subsequent therapy (p=0.697). Metastasectomy and/or local ablative treatment in the liver, lung, peritoneum and/or other organs were applied in 26 patients (22%) with curative intent. First-line anti-EGFR-based therapy showed a trend towards longer OS compared to anti-VEGF-based therapy or chemotherapy alone in left-sided mCRC (anti-EGFR: 39.3 months versus anti-VEGF: 27.3 months versus chemotherapy alone: 13.8 months, p=0.105). In multivariable analysis, metastasectomy and/or local ablative treatment with curative intent (yes versus no, HR: 0.22, p<0.001), the ECOG performance score (2 versus 0, HR: 3.07, p=0.007; 3 versus 0, HR: 3.66, p=0.053) and the presence of liver metastases (yes versus no, HR: 1.79, p=0.049) were independently associated with OS. Conclusions Our findings corroborate front-line monochemotherapy in combination with targeted therapy as the treatment of choice for elderly mCRC patients with palliative treatment intent. Metastasectomy and/or local ablative treatment with curative intent are feasible and may improve OS in selected elderly mCRC patients.


Introduction
Colorectal cancer (CRC) is the second most common cause of cancer-related death worldwide (1). The incidence rate of CRC considerably increases with age and age-standardized CRC mortality rates are highest among elderly patients (2,3). Elderly metastatic CRC (mCRC) patients (≥70 years) are underrepresented in clinical trials and one out of four elderly mCRC patients does not receive chemotherapy-based palliative systemic therapy due to comorbidities, chronological age or poor performance status (4).
Therapeutic decision making and treatment recommendations by the European Society of Medical Oncology (ESMO) (5) and National Comprehensive Cancer Network (NCCN) (6) for elderly mCRC patients are mainly based on a limited number of clinical trials focusing on the elderly mCRC population (7)(8)(9). Fluorouracil-based monochemotherapy in combination with anti-VEGF-based therapy irrespective of sidedness (7,9) or in combination with anti-EGFR-based therapy (8) as well as anti-EGFR monotherapy (10) in patients with RAS wild-type left-sided tumors represent recommended first-line protocols (5). A median overall survival of 14 and 21 months is achieved with the abovementioned first-line protocols among patients ≥75 years (10) and ≥70 years (7), respectively; however, data on the clinical outcome in the elderly mCRC population in the real-world setting are sparse.
While metastasectomy and/or local ablative treatment (+/perioperative chemotherapy or previous conversion therapy) represent established approaches in eligible patients with oligometastatic CRC (5,6), there is a paucity of evidence supporting this treatment concept with putative curative intent in the elderly oligometastatic CRC population.
The primary aim of this unicentric retrospective analysis was to evaluate the therapeutic management of mCRC patients ≥70 years of age and clinical outcome in a real-world setting. Furthermore, this analysis aimed at investigating the frequency, feasibility and efficacy of metastasectomy and/or local ablative treatment with putative curative intent in this elderly population.

Patients and methods Patients
This retrospective analysis was approved by the Ethics Committee of the provincial government of Salzburg, Austria (415-E/2343/5-2018). Patients with an age ≥70 years at the time point of histologically confirmed mCRC diagnosis and who received systemic therapy for mCRC at our tertiary cancer center (Department of Internal Medicine III, Paracelsus Medical University Salzburg, Austria) between February 2009 and July 2022 were included in this analysis. All included patients alive at the date of analysis signed an informed consent form. Early access within a named patient program was available for patients who had received regorafenib and/or TAS-102 before the respective approval by the European Medicines Agency (EMA). Data were extracted from medical records, including: In order to draw a comparison in regard to age distribution and treatment intent between our unicentric elderly mCRC cohort and mCRC patients ≥70 years in the province of Salzburg (Austria), data from the Tumor Registry of the Province of Salzburg from 2013 to 2020 were used.

Statistical analyses
Baseline characteristics were compared using crosstabulation together with the chi-squared test, in case of categorical data.
Continuous data were summarized using medians and ranges and compared between groups with the Mann-Whitney test. Uni-and multivariable analyses were based on Cox proportional hazard models. For multivariable analysis covariable selection, a backward stepwise procedure was performed using the Akaike information criterion (AIC) as selection criterion (11). OS was calculated from the date of mCRC diagnosis until death from any cause. Metastasectomy and/or local ablative treatment (yes versus no) as well as regorafenib and/or TAS-102 exposure were taken into account as time-dependent covariates, respectively. Patients alive at the last contact were censored. IBM SPSS Statistics version 27 (Armonk, NY, US) and the statistical software environment R (version 4.1.2, survival and MASS package) were used for statistical analyses. The complete data set is available from the corresponding author on reasonable request.

Baseline characteristics
In this retrospective monocentric analysis, 117 mCRC patients aged ≥70 years, diagnosed between February 2009 and July 2022, and undergoing systemic therapy for mCRC were included. The baseline characteristics are depicted in Table 1.
The median number of systemic therapy lines in the study population was 2 (range: 1-5) and 52%, 27% 12% and 3% received a second-line, third-line, fourth-line and fifth-line therapy ( Figure 1). The chemotherapy backbone in first line (mono versus doublet/ triplet) did not statistically significantly impact the probability of receiving subsequent therapy (p=0.697, Figure 1).
Patients undergoing metastasectomy and/or local ablative treatment were more likely to receive a front-line doublet or triplet chemotherapy backbone (89% versus 67%, p=0.035) and showed a trend towards metachronous metastases (38% versus 22%, p=0.090) compared to patients without ablative measures (Table A.3).

Age and treatment intent of elderly mCRC patients in the province of Salzburg
According to the Tumor Registry of the Province of Salzburg (Austria), the following age distribution pattern was found between 2013 and 2020 in the province of Salzburg among mCRC patients ≥70 years: 70-74 years: 32%; 75-79 years: 35%; 80-84 years: 33%, ≥85 years: 0%.

Systemic therapy
The chemotherapy backbone of front-line therapy did neither affect OS in the entire cohort (doublet or triplet versus monochemotherapy, HR: 0.83, p=0.50; Table 2), nor among patients without metastasectomy and/or local ablative treatment (HR: 1.11, p=0.73). The addition of an anti-EGFR or anti-VEGF monoclonal antibody to chemotherapy in first line irrespective of the primary tumor localization resulted in a trend towards longer survival (anti-EGFR: 29.7 months versus anti-VEGF: 27.3 months versus no targeted therapy: 13.3 months, p=0.15 log-rank, Figure 2B). The choice of targeted therapy according to sidedness in first-line was associated with a trend towards superior survival with anti-EGFR-based therapy in left-sided disease (anti-EGFR: 39.3 months versus anti-VEGF: 27.3 months versus no targeted  therapy: 13.8 months, p=0.105 log-rank; Figure 2D), while sidedness proved less predictive in right-sided disease (anti-VEGF: 27.1 months versus anti-EGFR: 11.2 months versus no targeted therapy: 10.6 months, p=0.325 log-rank; Figure 2C). The application of more systemic therapy lines was associated with improved OS (≥2 versus 1, HR: 0.40, p<0.001; Table 2). Patients receiving regorafenib and/or TAS-102 during the course of disease did not show a survival benefit (yes versus no, HR: 1.14, p=0.67; Table 2) when considered as a time-dependent covariate. Seven patients were treated within clinical trials in first line and three patients in subsequent therapy lines.

Discussion
As the aging population is highly represented among mCRC patients and due to the paucity of trial-based recommendations, therapeutic decision making in elderly mCRC patients remains challenging in clinical practice. In our unicentric, retrospective analysis we characterized patient and tumor characteristics and investigated clinical outcome in a representative elderly patient cohort undergoing systemic therapy for mCRC. The distribution of age categories within our elderly mCRC cohort was comparable to records of the Tumor Registry of the Province of Salzburg between 2013 and 2020: 70-74 years: 31% versus 32%; 75-79 years: 36% versus 35%; 80-84 years: 27% versus 33%, ≥85 years: 6% versus 0%. It is noteworthy, that only 59% of mCRC patients ≥70 years of age received palliative systemic therapy in the Province of Salzburg.
Based on the findings of our unicentric analysis we provide further evidence that OS of elderly mCRC patients undergoing systemic therapy in the real-world setting (mOS of 25.6 months) is comparable to landmark clinical trials (7, 12) (mOS of 19 to 21 months, Table A.4). Metastasectomy and/or local ablative treatment with curative intent proved feasible in selected elderly patients and resulted in a significant and clinically meaningful OS benefit (HR: 0.22, p<0.001, Figure 3). Furthermore, the observed trend towards superior OS with an anti-EGFR-based therapy in left-sided mCRC when compared to anti-VEGF-based therapy or chemotherapy alone ( Figure 2D) sheds further light on the predictive value of sidedness and corroborates the preference of anti-EGFR-based therapy also in elderly patients with RAS/BRAF wild-type leftsided disease.
The chemotherapy backbone in first line (doublet or triplet versus mono) did neither impact the number of subsequent therapy lines (p=0.697, Figure 1), nor had an impact on clinical outcome in  (16) or irinotecan (17) to 5-FU or capecitabine did not improve OS in elderly and/or frail mCRC patients, but significantly increased the frequency of grade 3-4 toxicities (17). In this regard, it is noteworthy that the ECOG PS in our elderly cohort was comparable to the study population of the MRC FOCUS2 trial (16): ECOG 0: 21%/21%, ECOG 1: 48%/50%, ECOG 2: 26%/29%, ECOG 3: 5%/0%. Higher treatment-related toxicity rates with a doublet chemotherapy backbone and a higher frequency of comorbidities have also been observed with increasing age in the CALGB 80405 study (18). Age demonstrated as a considerable prognostic factor in the FIRE-3 study (19) (≥65 years: 25.9 versus <65 years: 29.3 months, p=0.02) and CALGB 80405 study (18) (≥70 years versus <70 years: HR 1.32, p<0.001). Within our study population (range: 70-90 years), older patients showed a trend towards a worse ECOG PS (p=0.087), however, age as a continuous parameter did not show any additional prognostic value among mCRC patients ≥70 years (Table 2).
A worse ECOG PS at mCRC diagnosis showed a statistically significant and independent association with inferior OS (2 versus 0, HR: 3.07; 3 versus 0: HR; 3.66; Figure 3). While classification into the ECOG PS categories (from 0: fully active to 4: completely disabled) can be rapidly performed in daily clinical practice in younger patients, the latter performance score assessment can be challenging in elderly cancer patients due to physicians' varying conception of the usual performance spectrum of elderly people. Considerable disparities between patient-reported and physicianreported ECOG PS ratings exist (20) and there is also a poor agreement in ECOG PS ratings between clinicians (21). Other scores such as the Charlson Comorbidity Index (22), which includes age and multiple comorbidities and classifies into four risk categories, proved as predictors of survival in (m)CRC (23)(24)(25). However, our findings confirm the ECOG PS as a time-saving prognosticator and helpful tool for therapeutic decision-making (e.g. chemotherapy intensity) in daily clinical practice in elderly mCRC patients. The International Society of Geriatric Oncology recommends geriatric assessment in older cancer patients aiming at influencing treatment choice, predicting treatment-related complications and predicting clinical outcome. Geriatric assessment should include functional status, comorbidities, cognition, mental health status, fatigue, social status and support, nutrition, and the presence of geriatric syndromes (26). Based on the retrospective nature of our analysis, only the functional status was extracted from medical records and geriatric assessment was not feasible.
Contrary to the literature (27), sidedness was not prognostic among elderly mCRC patients in our cohort (left-sided versus rightsided, HR: 1.10 p=0.71, Figure 2A), which may be explained by the  (19). Liver surgery for colorectal metastases with curative intent in elderly mCRC patients can yield a comparable OS benefit as in the young population (28, 29). For elderly mCRC patients undergoing CRC liver metastases resection an incidence of 60-to 90-day mortality ranging between 4% and 8% has been reported in population-based studies (29,30).
According to the RAXO study, a nationwide Finnish prospective intervention study, up to 41% of mCRC patients can be classified as resectable with curative intent either upfront or after conversion therapy irrespective of chronological age (31). In our cohort, metastasectomy and/or local ablative treatment were performed in 22% of patients with technically resectable disease extent and adequate performance status and yielded a clinically meaningful and independent OS benefit (HR: 0.22, Figure 3). This is in line with the secondary metastasectomy rate (18%) and the OS advantage (HR: 0.44) of elderly patients in the FIRE-3 study (19). The latter findings should encourage us to identify eligible patients for metastasectomy and/or local ablative treatment with curative intent in the elderly mCRC population. The presence of liver metastases was a significant and independent negative prognostic factor (HR: 1.79, p=0.05)presumably mainly driven by non-resectable and non-liverlimited disease.
However, we would like to emphasize that in the FIRE-3 and CALGB 80405 studies elderly patients were defined by ≥65 years and ≥70 years, respectively, and were all deemed fit for a doublet chemotherapy backbone (18,19). Data from the Cardiovascular Health Study corroborate an increasing prevalence of frailty with higher chronological age (32). Therefore, the FIRE-3 and CALGB 80405 mCRC populations may not properly reflect the elderly and often frail mCRC population in the real-world setting.
Within the inclusion period of our retrospective analysis (2009-2022), regorafenib (33) as well as TAS-102 (34) have been established as EMA-and FDA-approved third-line therapy options based on a survival benefit versus placebo, respectively. In our cohort, one out of five patients received regorafenib and/or TAS-102 during the course of disease (Table 1). Since the availability of regorafenib and TAS-102 within named patient programs or based on the respective EMA approval, our treatment strategy has not favored one drug over the other in the time interval between 2014 and 2022 ( Figure A.1). However, based on the toxicity profile of regorafenib (33), an increased skeletal muscle loss (35) and a higher frequency of hospitalizations with regorafenib compared to TAS-102 (36), regorafenib should be used with caution in elderly mCRC patients. Treatment with regorafenib and/or TAS-102 did not result in a survival advantage when taken into account as a time-dependent covariate (yes versus no, HR: 1.09, p=0.79, Figure 3). According to the ESMO Magnitude of Clinical Benefit Scale (ESMO-MCBS) (37), which is based on the extent of OS gain, QoL and toxicities, TAS-102 (MCBS: 3) proved superior to regorafenib (MCBS: 1) (5).
The SUNLIGHT study, a randomized phase 3 study comparing TAS-102 versus TAS-102 in combination with bevacizumab for third-line treatment of refractory mCRC, has met its primary endpoint, demonstrating an OS benefit with TAS-102 plus bevacizumab (10.8 months versus 7.5 months, HR: 0.61, p<0.001) (38). Due to the acceptable safety profile of TAS-102 combined with bevacizumab in previous studies (9,38,39)   Multivariable analysis for overall survival -Forest Plot. ECOG performance score: Eastern Cooperative Oncology Group performance score. Regorafenib and/or TAS-102 exposure as well as metastasectomy and/or local ablative treatment were taken into consideration as time-dependent covariates. *involved organs: liver, lung, peritoneum, other.
compared to the experimental arm of the AVEX trial (7) (mOS of 20.7 months, Table A.4).
Potential limitations of our study include the retrospective nature and the length of the inclusion period (2009)(2010)(2011)(2012)(2013)(2014)(2015)(2016)(2017)(2018)(2019)(2020)(2021)(2022). Within the latter time span, biomarker refinement for established therapies (42), numerous new therapies for all-comers (33,34) and biomarker-defined targeted-therapies (40,41) changed daily clinical practice resulting in heterogenous treatments strategies in our elderly mCRC cohort. As a consequence, the predictive biomarker status is incomplete in a relevant number of patients. Furthermore, the implementation of sidedness into first-line decision making took place after the Annual ASCO Meeting 2016 (27,43,44), therefore, sidedness as a predictive biomarker could only be applied in less than half of our elderly mCRC patients. It is noteworthy, that elderly patients undergoing only a best supportive care strategy were excluded from our analysis. Although the number of included patients in our analysis (n=117) was limited, the sample size was comparable to the experimental arms of the AVEX (n=140) and PANDA (n=93) landmark trials (Table A.

Conclusions
Clinical outcome among real-world elderly (≥70 years) mCRC patients is comparable to the results of first-line elderly mCRC landmark trials. First-line monochemotherapy plus targeted therapy based on sidedness and molecular status should be the treatment of choice. Based on proper patient selection, one out of five elderly mCRC patients qualifies for metastasectomy and/or local ablative treatment with curative intent. A doublet chemotherapy backbone +/-targeted therapy may be expedient in elderly mCRC patients who are candidates for metastasectomy and/or local ablative treatment. The latter ablative measures are feasible and yield a clinically meaningful survival benefit in selected elderly mCRC patients.

Data availability statement
The raw data supporting the conclusions of this article will be made available by the authors on reasonable request.

Ethics statement
The studies involving human participants were reviewed and approved by the Ethics Committee of the provincial government of Salzburg, Austria (415-E/2343/5-2018). Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.

Funding
This work was supported by Servier Austria GmbH without any role in the design of the analysis, interpretation of data or influence on the content of the manuscript. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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Supplementary material
The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fonc.2023.1222951/ full#supplementary-material SUPPLEMENTARY TABLE 1 Association between 1L chemotherapy backbone and ECOG PS as well as age at mCRC diagnosis.

SUPPLEMENTARY TABLE 3
Comparison of baseline characteristics between elderly mCRC patients undergoing metastasectomy and/or local ablative treatment versus not # Mann-Whitney-U-Test. ECOG, Eastern Cooperative Oncology Group, mCRC, metastatic colorectal cancer.

SUPPLEMENTARY TABLE 4
Comparison of baseline characteristics and clinical outcome between the Salzburg elderly mCRC real-world cohort and elderly mCRC landmark trials.